Chlorinated tetralin compounds and pharmaceutical compositions

ABSTRACT

The present disclosures are directed to chlorinated tetralin compounds and pharmaceutical compositions.

REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Non Provisionalapplication Ser. No. 17/860,682, filed Jul. 8, 2022 and claims prioritybenefit to U.S. Provisional Application No. 63/241,844, filed Sep. 8,2021, U.S. Provisional Application No. 63/263,635, filed Nov. 5, 2021,and U.S. Provisional Application No. 63/365,125, filed May 20, 2022which is each hereby incorporated by reference in its entirety.

FIELD OF THE DISCLOSURE

The present disclosure relates to chlorinated tetralin compounds andpharmaceutical compositions comprising them. The pharmaceuticalcompositions can comprise a chlorinated tetralin compound and agamma-secretase inhibitor, such as nirogacestat.

BACKGROUND

Chlorinated tetralin compounds can be generated during a syntheticprocess of(S)-2-((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide(“nirogacestat”). Nirogacestat exhibits promising activity for thetreatment of tumors or cancer, such as desmoid tumors, multiple myeloma,a cancer having a mutation in a Notch pathway gene, adenoid cysticcarcinoma, and T-cell acute lymphoblastic leukemia.

BRIEF SUMMARY OF THE DISCLOSURE

The disclosure relates to a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³ and R⁴are individually hydrogen or halogen, and at least one of R¹, R², R³ andR⁴ is chloro.

In some aspects, the compound of Formula I is selected from the groupconsisting of(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide,(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide, and(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide.

In some aspects, the compound of Formula I is that of Formula IA

or a pharmaceutically acceptable salt thereof.

In some aspects, the compound of Formula I is that of Formula IB

or a pharmaceutically acceptable salt thereof.

In some aspects, the compound of Formula I is that of Formula IC

or a pharmaceutically acceptable salt thereof.

The disclosure further relates to a pharmaceutical compositioncomprising a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³ and R⁴are individually hydrogen or halogen, and at least one of R¹, R², R³ andR⁴ is chloro.

In some aspects, the pharmaceutical composition comprises a compound ofFormula I selected from the group consisting of(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide,(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide, and(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide.

In some aspects, the compound of Formula I or pharmaceuticallyacceptable salt thereof in the pharmaceutical composition is present inan amount of about 1 μg to about 500 μg. In some aspects, the compoundof Formula I or pharmaceutically acceptable salt thereof in thepharmaceutical composition is present in an amount of about 5 μg toabout 500 μg. In some aspects, the compound of Formula I orpharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 250 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 100 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 50 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 12.5 μg to about 50 μg. In some aspects, the pharmaceuticalcomposition comprising a compound of Formula I or pharmaceuticallyacceptable salt thereof further comprises a gamma-secretase inhibitorselected from the group consisting of nirogacestat, or apharmaceutically acceptable salt thereof, crenigacestat, or apharmaceutically acceptable salt thereof, AL101, or a pharmaceuticallyacceptable salt thereof, AL102, or a pharmaceutically acceptable saltthereof, semagacestat, or a pharmaceutically acceptable salt thereof,avagacestat, and ianabecestat, or a pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition comprising acompound of Formula I or pharmaceutically acceptable salt thereoffurther comprises nirogacestat, or a pharmaceutically acceptable saltthereof.

The disclosure further relates to a pharmaceutical compositioncomprising a compound of Formula I which is that of Formula IA

or a pharmaceutically acceptable salt thereof. In some aspects, thecompound of Formula IA or pharmaceutically acceptable salt thereof inthe pharmaceutical composition is present in an amount of about 1 μg toabout 500 μg. In some aspects, the compound of Formula IA orpharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 5 μg to about 500 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 250 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 100 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 50 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 12.5 μg to about 50 μg. Insome aspects, the pharmaceutical composition comprising a compound ofFormula IA or pharmaceutically acceptable salt thereof further comprisesa gamma-secretase inhibitor selected from the group consisting ofnirogacestat, or a pharmaceutically acceptable salt thereof,crenigacestat, or a pharmaceutically acceptable salt thereof, AL101, ora pharmaceutically acceptable salt thereof, AL102, or a pharmaceuticallyacceptable salt thereof, semagacestat, or a pharmaceutically acceptablesalt thereof, avagacestat, or a pharmaceutically acceptable saltthereof, and ianabecestat or a pharmaceutically acceptable salt thereof.In some aspects, the pharmaceutical composition comprising a compound ofFormula IA or pharmaceutically acceptable salt thereof further comprisesnirogacestat, or a pharmaceutically acceptable salt thereof.

The disclosure further relates to a pharmaceutical compositioncomprising a compound of Formula I which is that of Formula IB

or a pharmaceutically acceptable salt thereof. In some aspects, thecompound of Formula IB or pharmaceutically acceptable salt thereof inthe pharmaceutical composition is present in an amount of about 1 μg toabout 500 μg. In some aspects, the compound of Formula IB orpharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 5 μg to about 500 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 250 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 100 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 50 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 12.5 μg to about 50 μg. Insome aspects, the pharmaceutical composition comprising a compound ofFormula IB or pharmaceutically acceptable salt thereof further comprisesa gamma-secretase inhibitor selected from the group consisting ofnirogacestat, or a pharmaceutically acceptable salt thereof,crenigacestat, or a pharmaceutically acceptable salt thereof, AL101, ora pharmaceutically acceptable salt thereof, AL102, or a pharmaceuticallyacceptable salt thereof, semagacestat, or a pharmaceutically acceptablesalt thereof, avagacestat, or a pharmaceutically acceptable saltthereof, and ianabecestat, or a pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition comprising acompound of Formula IB or pharmaceutically acceptable salt thereoffurther comprises nirogacestat, or a pharmaceutically acceptable saltthereof.

The disclosure further relates to a pharmaceutical compositioncomprising a compound of Formula I which is a compound of Formula IC

or a pharmaceutically acceptable salt thereof. In some aspects, thecompound of Formula IC in the pharmaceutical composition is present inan amount of about 1 μg to about 500 μg. In some aspects, the compoundof Formula IC in the pharmaceutical composition is present in an amountof about 5 μg to about 500 μg. In some aspects, the compound of FormulaIC in the pharmaceutical composition is present in an amount of about 10μg to about 250 μg. In some aspects, the compound of Formula IC in thepharmaceutical composition is present in an amount of about 10 μg toabout 100 μg. In some aspects, the compound of Formula IC in thepharmaceutical composition is present in an amount of about 10 μg toabout 50 μg. In some aspects, the compound of Formula IC in thepharmaceutical composition is present in an amount of about 12.5 μg toabout 50 μg. In some aspects, the pharmaceutical composition comprisinga compound of Formula IC further comprises a gamma-secretase inhibitorselected from the group consisting of nirogacestat, or apharmaceutically acceptable salt thereof, crenigacestat, or apharmaceutically acceptable salt thereof, AL101, or a pharmaceuticallyacceptable salt thereof, AL102, or a pharmaceutically acceptable saltthereof, semagacestat, or a pharmaceutically acceptable salt thereof,avagacestat, or a pharmaceutically acceptable salt thereof, andianabecestat, or a pharmaceutically acceptable salt thereof. In someaspects, the pharmaceutical composition comprising a compound of FormulaIC further comprises nirogacestat, or a pharmaceutically acceptable saltthereof.

In some aspects, the pharmaceutical composition comprising a compound ofFormula I, Formula IA, Formula IB, or Formula IC further comprises apharmaceutically acceptable carrier. In some aspects, the pharmaceuticalcomposition comprising a compound of Formula I, Formula IA, Formula IB,or Formula IC is for oral administration. In some aspects, thepharmaceutical composition comprising a compound of Formula I, FormulaIA, Formula IB, or Formula IC is a tablet.

The present disclosure further relates to methods of treating tumorscomprising administering to a subject in need of such treatment apharmaceutical composition comprising a compound of Formula I, FormulaIA, Formula IB, or Formula IC. In some aspects, the tumors are desmoidtumors.

The present disclosure further relates to methods of treating cancercomprising administering to a subject in need of such treatment, apharmaceutical composition comprising a compound of Formula I, FormulaIA, Formula IB, or Formula IC. In some aspects, the cancer is selectedfrom the group consisting of multiple myeloma, a cancer having amutation in a Notch pathway gene, adenoid cystic carcinoma, and T-cellacute lymphoblastic leukemia.

DETAILED DESCRIPTION I. Definitions and Abbreviations

As used above, and throughout the description, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings.

Unless stated otherwise, the terms “a” and “an” and “the” and similarreferences used in the context of describing a particular aspect of theapplication (especially in the context of claims) can be construed tocover both the singular and the plural. The recitation of ranges ofvalues herein is merely intended to serve as a shorthand process ofreferring individually to each separate value falling within the range.Unless otherwise indicated herein, each individual value is incorporatedinto the specification as if it were individually recited herein.

The term “pharmaceutical composition,” as used herein, represents acomposition containing a compound described herein formulated with apharmaceutically acceptable excipient, and can be manufactured or soldwith the approval of a governmental regulatory agency as part of atherapeutic regimen for the treatment of disease in a mammal.Pharmaceutical compositions can be formulated, for example, for oraladministration in unit dosage form (e.g., a tablet, capsule, caplet,gelcap, or syrup); for topical administration (e.g., as a cream, gel,lotion, or ointment); for intravenous administration (e.g., as a sterilesolution free of particulate emboli and in a solvent system suitable forintravenous use); for intrathecal injection; for intracerebroventricularinjections; for intraparenchymal injection; or in any otherpharmaceutically acceptable formulation.

The terms “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refer to a pharmaceuticallyacceptable material, composition, or vehicle, such as a liquid or solidfiller, diluent, excipient, solvent, or encapsulating material. In oneaspect, each component is “pharmaceutically acceptable” in the sense ofbeing compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See Remington: TheScience and Practice of Pharmacy, 21^(st) Edition, Lippincott Williams &Wilkins Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,5^(th) Edition, Rowe et al., Eds., The Pharmaceutical Press and theAmerican Pharmaceutical Association: 2005; and Handbook ofPharmaceutical Additives, 3^(rd) Edition, Ash and Ash Eds., GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004 (incorporated hereinby reference). Excipients can include, for example: antiadherents,antioxidants, binders, coatings, compression aids, disintegrants, dyes(colors), emollients, emulsifiers, fillers (diluents), film formers orcoatings, flavors, fragrances, glidants (flow enhancers), lubricants,preservatives, printing inks, sorbents, suspensing or dispersing agents,sweeteners, and waters of hydration. Exemplary excipients include, butare not limited to: butylated hydroxytoluene (BHT), calcium carbonate,calcium phosphate (dibasic), calcium stearate, croscarmellose,crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine,ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol,methionine, methylcellulose, methyl paraben, microcrystalline cellulose,polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinizedstarch, propyl paraben, retinyl palmitate, shellac, silicon dioxide,sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate,sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide,vitamin A, vitamin E, vitamin C, and xylitol.

The term “pharmaceutically-acceptable salts” refers to the relativelynon-toxic, inorganic and organic acid addition salts of Compound A orCompound B. These salts can be prepared in situ in the administrationvehicle or the dosage form manufacturing process, or by separatelyreacting a purified compound of the invention in its free base form witha suitable organic or inorganic acid, and isolating the salt thus formedduring subsequent purification. Representative salts include thehydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate,acetate, valerate, oleate, palmitate, stearate, laurate, benzoate,lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate,tartrate, napthylate, mesylate, glucoheptonate, lactobionate, andlaurylsulphonate salts and the like. (See, e.g., Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

The pharmaceutically acceptable salts of the subject compounds includethe conventional nontoxic salts or quaternary ammonium salts of thecompounds, e.g., from non-toxic organic or inorganic acids. For example,such conventional nontoxic salts include those derived from inorganicacids such as hydrochloride, hydrobromic, sulfuric, sulfamic,phosphoric, nitric, and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic, and the like.

In certain aspects, the compounds of the present invention may containone or more acidic functional groups and, thus, are capable of formingpharmaceutically acceptable salts with pharmaceutically acceptablebases. The term “pharmaceutically-acceptable salts” in these instancesrefers to the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present invention. These salts can likewise beprepared in situ in the administration vehicle or the dosage formmanufacturing process, or by separately reacting the purified compoundin its free acid form with a suitable base, such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cation,with ammonia, or with a pharmaceutically acceptable organic primary,secondary or tertiary amine. Representative alkali or alkaline earthsalts include the lithium, sodium, potassium, calcium, magnesium, andaluminum salts and the like. Representative organic amines useful forthe formation of base addition salts include ethylamine, diethylamine,ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.(See, e.g., Berge et al., supra).

The terms “about” or “approximately” means within a range of anacceptable error for a particular value as determined by one of ordinaryskill in the art, which depends in part on how the value is measured ordetermined. In certain aspects, the term “about” or “approximately”means within 1, 2, 3, or 4 standard deviations. In some aspects, theterm “about” or “approximately” means a quantity, level, value, number,frequency, percentage, dimension, size, amount, weight or length thatvaries by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% toa reference quantity, level, value, number, frequency, percentage,dimension, size, amount, weight or length.

As used herein, the term “administration” refers to the administrationof a composition (e.g., a compound or a preparation that includes acompound as described herein) to a subject or system. Administration toan animal subject (e.g., to a human) can be by any appropriate route,such as one described herein.

The terms “comprise,” “comprises,” and “comprising” are used on thebasis and clear understanding that they are to be interpretedinclusively, rather than exclusively.

II. Chlorinated Tetralin Compounds

The disclosure relates to a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³ and R⁴are individually hydrogen or halogen, and at least one of R¹, R², R³ andR⁴ is chloro. In some aspects, R¹ is chloro, and R², R³ and R⁴ areindividually hydrogen or halogen. In some aspects, R² is chloro, and R¹,R³ and R⁴ are individually hydrogen or halogen. In some aspects, R³ ischloro, and R¹, R² and R⁴ are individually hydrogen or halogen. In someaspects, R⁴ is chloro, and R¹, R² and R³ are individually hydrogen orhalogen. In some aspects, R¹ and R² are individually chloro, and R³ andR⁴ are individually hydrogen or halogen. In some aspects, R¹ and R³ areindividually chloro, and R² and R⁴ are individually hydrogen or halogen.In some aspects, R¹ and R⁴ are chloro, and R² and R³ are hydrogen orhalogen. In some aspects, R² and R³ are chloro, and R¹ and R⁴ arehydrogen or halogen. In some aspects, R² and R⁴ are individually chloro,and R¹ and R³ are individually hydrogen or halogen. In some aspects, R³and R⁴ are individually chloro, and R¹ and R² are individually hydrogenor halogen. In some aspects, R¹, R² and R³ are individually chloro, andR⁴ is hydrogen or halogen. In some aspects, R¹, R² and R⁴ areindividually chloro, and R³ is hydrogen or halogen. In some aspects, R¹,R³ and R⁴ are individually chloro, and R² is hydrogen or halogen. Insome aspects, R², R³ and R⁴ are individually chloro, and R¹ is hydrogenor halogen. In some aspects, R¹, R², R³ and R⁴ are individually chloro.

In some aspects, the compound of Formula I is selected from the groupconsisting of(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide,(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide, and(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide.

In some aspects, the compound of Formula I is(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide.

In some aspects, the compound of Formula I is(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide.

In some aspects, the compound of Formula I is(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide.

In some aspects, the compound of Formula I is that of Formula IA

or a pharmaceutically acceptable salt thereof.

In some aspects, the compound of Formula I is that of Formula IB

or a pharmaceutically acceptable salt thereof.

In some aspects, the compound of Formula I is that of Formula IC

or a pharmaceutically acceptable salt thereof.

In some aspects, the compound of Formula I, Formula IA, Formula IB, andFormula IC is in the free base form.

In some aspects, the compound of Formula I, Formula IA, Formula IB, andFormula IC is in a pharmaceutically acceptable salt form. In someaspects, the pharmaceutically acceptable salt form of the compound ofFormula I, Formula IA, Formula IB, and Formula IC is a hydrobromide saltform. In some aspects, the pharmaceutically acceptable salt form of thecompound of Formula I, Formula IA, Formula IB, and Formula IC is adihydrobromide salt form.

III. Pharmaceutical Compositions

The disclosure further relates to a pharmaceutical compositioncomprising a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³ and R⁴are individually hydrogen or halogen, and at least one of R¹, R², R³ andR⁴ is chloro. In some aspects, the pharmaceutical composition comprisesa compound of Formula I or a pharmaceutically acceptable salt thereof,wherein R¹ is chloro, and R², R³ and R⁴ are individually hydrogen orhalogen. In some aspects, the pharmaceutical composition comprises acompound of Formula I or a pharmaceutically acceptable salt thereof,wherein R² is chloro, and R¹, R³ and R⁴ are individually hydrogen orhalogen. In some aspects, the pharmaceutical composition comprises acompound of Formula I or a pharmaceutically acceptable salt thereof,wherein R³ is chloro, and R¹, R² and R⁴ are individually hydrogen orhalogen. In some aspects, the pharmaceutical composition comprises acompound of Formula I or a pharmaceutically acceptable salt thereof,wherein R⁴ is chloro, and R¹, R² and R³ are individually hydrogen orhalogen. In some aspects, the pharmaceutical composition comprises acompound of Formula I or a pharmaceutically acceptable salt thereof,wherein R¹ and R² are chloro, and R³ and R⁴ are individually hydrogen orhalogen. In some aspects, the pharmaceutical composition comprises acompound of Formula I or a pharmaceutically acceptable salt thereof,wherein R¹ and R³ are individually chloro, and R² and R⁴ areindividually hydrogen or halogen. In some aspects, the pharmaceuticalcomposition comprises a compound of Formula I or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R⁴ are individually chloro, andR² and R³ are individually hydrogen or halogen. In some aspects, thepharmaceutical composition comprises a compound of Formula I or apharmaceutically acceptable salt thereof, wherein R² and R³ areindividually chloro, and R¹ and R⁴ are individually hydrogen or halogen.In some aspects, the pharmaceutical composition comprises a compound ofFormula I or a pharmaceutically acceptable salt thereof, wherein R² andR⁴ are individually chloro, and R¹ and R³ are individually hydrogen orhalogen. In some aspects, the pharmaceutical composition comprises acompound of Formula I or a pharmaceutically acceptable salt thereof,wherein R³ and R⁴ are individually chloro, and R¹ and R² areindividually hydrogen or halogen. In some aspects, the pharmaceuticalcomposition comprises a compound of Formula I or a pharmaceuticallyacceptable salt thereof, wherein R¹, R² and R³ are individually chloro,and R⁴ is hydrogen or halogen. In some aspects, the pharmaceuticalcomposition comprises a compound of Formula I or a pharmaceuticallyacceptable salt thereof, wherein R¹, R² and R⁴ are individually chloro,and R³ is hydrogen or halogen. In some aspects, the pharmaceuticalcomposition comprises a compound of Formula I or a pharmaceuticallyacceptable salt thereof, wherein R¹, R³ and R⁴ are individually chloro,and R² is hydrogen or halogen. In some aspects, the pharmaceuticalcomposition comprises a compound of Formula I or a pharmaceuticallyacceptable salt thereof, wherein R², R³ and R⁴ are individually chloro,and R′ is hydrogen or halogen. In some aspects, the pharmaceuticalcomposition comprises a compound of Formula I or a pharmaceuticallyacceptable salt thereof, wherein R¹, R², R³ and R⁴ are individuallychloro.

In some aspects, the compound of Formula I or pharmaceuticallyacceptable salt thereof in the pharmaceutical composition is present inan amount of about 1 μg to about 500 μg. In some aspects, the compoundof Formula I or pharmaceutically acceptable salt thereof in thepharmaceutical composition is present in an amount of about 2 μg toabout 500 μg. In some aspects, the compound of Formula I orpharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 3 μg to about 500 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 4 μg to about 500 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 5 μg to about 500 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 6 μg to about 475 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 6 μg to about 450 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 7 μg to about 425 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 7 μg to about 400 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 8 μg to about 375 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 8 μg to about 350 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 9 μg to about 325 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 9 μg to about 300 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 275 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 250 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 225 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 200 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 175 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 150 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 125 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 100 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 90 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 80 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 70 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 60 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 50 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 11 μg to about 50 μg. Insome aspects, the compound of Formula I or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 12 μg to about 50 μg. In some aspects, the compound of FormulaI or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 12.5 μg to about 50 μg.

In some aspects, the pharmaceutical composition comprising a compound ofFormula I or pharmaceutically acceptable salt thereof further comprisesa gamma-secretase inhibitor selected from the group consisting ofnirogacestat, or a pharmaceutically acceptable salt thereof,crenigacestat, or a pharmaceutically acceptable salt thereof, AL101, ora pharmaceutically acceptable salt thereof, AL102, or a pharmaceuticallyacceptable salt thereof, semagacestat, or a pharmaceutically acceptablesalt thereof, avagacestat, or a pharmaceutically acceptable saltthereof, and ianabecestat, or a pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition comprising acompound of Formula I or pharmaceutically acceptable salt thereoffurther comprises nirogacestat, or a pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition comprising acompound of Formula I or pharmaceutically acceptable salt thereoffurther comprises crenigacestat, or a pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition comprising acompound of Formula I or pharmaceutically acceptable salt thereoffurther comprises AL101, or a pharmaceutically acceptable salt thereof.In some aspects, the pharmaceutical composition comprising a compound ofFormula I or pharmaceutically acceptable salt thereof further comprisesAL102, or a pharmaceutically acceptable salt thereof. In some aspects,the pharmaceutical composition comprising a compound of Formula I orpharmaceutically acceptable salt thereof further comprises semagacestat,or a pharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising a compound of Formula I orpharmaceutically acceptable salt thereof further comprises avagacestat,or a pharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising a compound of Formula I orpharmaceutically acceptable salt thereof further comprises ianabecestat,or a pharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising a compound of Formula I orpharmaceutically acceptable salt thereof further comprises nirogacestathydrobromide. In some aspects, the pharmaceutical composition comprisinga compound of Formula I or pharmaceutically acceptable salt thereoffurther comprises nirogacestat dihydrobromide.

In some aspects, the pharmaceutical composition comprises a compound ofFormula I or pharmaceutically acceptable salt thereof selected from thegroup consisting of(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide,(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide, and(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide.

In some aspects, the pharmaceutical composition comprises a compound ofFormula I or pharmaceutically acceptable salt thereof that is(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 1 μg to about 500 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 2 μg to about 500 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 3 μg to about 500 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 4 μg to about 500 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 5 μg to about 500 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 6 μg to about 475 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 6 μg to about 450 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 7 μg to about 425 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 7 μg to about 400 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 8 μg to about 375 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 8 μg to about 350 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 9 μg to about 325 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 9 μg to about 300 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 275 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 250 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 225 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 200 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 175 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 150 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 125 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 100 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 90 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 80 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 70 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 60 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 50 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 11 μg to about 50 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 12 μg to about 50 μg. In some aspects, the(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 12.5 μg to about 50 μg.

In some aspects, the pharmaceutical composition comprising(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises a gamma-secretase inhibitor selectedfrom the group consisting of nirogacestat, or a pharmaceuticallyacceptable salt thereof, crenigacestat, or a pharmaceutically acceptablesalt thereof, AL101, or a pharmaceutically acceptable salt thereof,AL102, or a pharmaceutically acceptable salt thereof, semagacestat, or apharmaceutically acceptable salt thereof, avagacestat, or apharmaceutically acceptable salt thereof, and ianabecestat, or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises nirogacestat, or a pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises crenigacestat, or a pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises AL101, or a pharmaceutically acceptablesalt thereof. In some aspects, the pharmaceutical composition comprising(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises AL102, or a pharmaceutically acceptablesalt thereof. In some aspects, the pharmaceutical composition comprising(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises semagacestat. In some aspects, thepharmaceutical composition comprising(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises avagacestat, or a pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises ianabecestat, or a pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises nirogacestat hydrobromide. In someaspects, the pharmaceutical composition comprising(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises nirogacestat dihydrobromide.

In some aspects, the pharmaceutical composition comprises a compound ofFormula I that is(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 1 μg to about 500 μg. In some aspects,(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 2 μg to about 500 μg. In some aspects,the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 3 μg to about 500 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 4 μg to about 500 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 5 μg to about 500 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 6 μg to about 475 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 6 μg to about 450 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 7 μg to about 425 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 7 μg to about 400 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 8 μg to about 375 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 8 μg to about 350 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 9 μg to about 325 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 9 μg to about 300 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 275 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 250 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 225 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 200 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 175 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 150 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 125 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 100 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 90 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 80 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 70 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 60 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 50 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 11 μg to about 50 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 12 μg to about 50 μg. In some aspects, the(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 12.5 μg to about 50 μg.

In some aspects, the pharmaceutical composition comprising(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises a gamma-secretase inhibitor selectedfrom the group consisting of nirogacestat, crenigacestat, AL101, AL102,semagacestat, avagacestat, and ianabecestat. In some aspects, thepharmaceutical composition comprising(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises nirogacestat, or a pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises crenigacestat, or pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises AL101, or pharmaceutically acceptablesalt thereof. In some aspects, the pharmaceutical composition comprising(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises AL102, or pharmaceutically acceptablesalt thereof. In some aspects, the pharmaceutical composition comprising(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises semagacestat, or pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises avagacestat. In some aspects, thepharmaceutical composition comprising(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises ianabecestat, or pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises nirogacestat hydrobromide. In someaspects, the pharmaceutical composition comprising(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises nirogacestat dihydrobromide.

In some aspects, the pharmaceutical composition comprises a compound ofFormula I that is(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 1 μg to about 500 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 2 μg to about 500 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 3 μg to about 500 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 4 μg to about 500 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 5 μg to about 500 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 6 μg to about 475 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 6 μg to about 450 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 7 μg to about 425 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 7 μg to about 400 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 8 μg to about 375 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 8 μg to about 350 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 9 μg to about 325 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 9 μg to about 300 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 275 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 250 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 225 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 200 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 175 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 150 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 125 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 100 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 90 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 80 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 70 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 60 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 10 μg to about 50 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 11 μg to about 50 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 12 μg to about 50 μg. In some aspects, the(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide in the pharmaceutical composition is present in an amountof about 12.5 μg to about 50 μg.

In some aspects, the pharmaceutical composition comprising(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises a gamma-secretase inhibitor selectedfrom the group consisting of nirogacestat, or a pharmaceuticallyacceptable salt thereof, crenigacestat, or a pharmaceutically acceptablesalt thereof, AL101, or a pharmaceutically acceptable salt thereof,AL102, or a pharmaceutically acceptable salt thereof, semagacestat, or apharmaceutically acceptable salt thereof, avagacestat, and ianabecestat,or a pharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises nirogacestat, or a pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises crenigacestat, or pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises AL101, or pharmaceutically acceptablesalt thereof. In some aspects, the pharmaceutical composition comprising(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises AL102, or pharmaceutically acceptablesalt thereof. In some aspects, the pharmaceutical composition comprising(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises semagacestat, or pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises avagacestat, or pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises ianabecestat, or pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises nirogacestat hydrobromide. In someaspects, the pharmaceutical composition comprising(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide further comprises nirogacestat dihydrobromide

The disclosure further relates to a pharmaceutical compositioncomprising a compound of Formula I which is the compound of Formula IA

or a pharmaceutically acceptable salt thereof. In some aspects, thecompound of Formula IA or pharmaceutically acceptable salt thereof inthe pharmaceutical composition is present in an amount of about 1 μg toabout 500 μg. In some aspects, the compound of Formula IA orpharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 2 μg to about 500 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 3 μg to about 500 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 4 μg to about 500 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 5 μg to about 500 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 6 μg to about 475 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 6 μg to about 450 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 7 μg to about 425 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 7 μg to about 400 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 8 μg to about 375 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 8 μg to about 350 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 9 μg to about 325 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 9 μg to about 300 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 275 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 250 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 225 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 200 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 175 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 150 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 125 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 100 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 90 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 80 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 70 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 60 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 50 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 11 μg to about 50 μg. In some aspects, the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 12 μg to about 50 μg. Insome aspects, the compound of Formula IA or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 12.5 μg to about 50 μg.

In some aspects, the pharmaceutical composition comprising a compound ofFormula IA or pharmaceutically acceptable salt thereof further comprisesa gamma-secretase inhibitor selected from the group consisting ofnirogacestat, or a pharmaceutically acceptable salt thereof,crenigacestat, or a pharmaceutically acceptable salt thereof, AL101, ora pharmaceutically acceptable salt thereof, AL102, or a pharmaceuticallyacceptable salt thereof, semagacestat, or a pharmaceutically acceptablesalt thereof, avagacestat, or a pharmaceutically acceptable saltthereof, and ianabecestat, or a pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition comprisingFormula IA further comprises nirogacestat, or pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising Formula IA further comprises crenigacestat, orpharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising Formula IA further comprisesAL101, or pharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising Formula IA further comprisesAL102, or pharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising Formula IA further comprisessemagacestat, or pharmaceutically acceptable salt thereof. In someaspects, the pharmaceutical composition comprising Formula IA furthercomprises avagacestat, or pharmaceutically acceptable salt thereof. Insome aspects, the pharmaceutical composition comprising Formula IAfurther comprises ianabecestat, or pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition comprising acompound of Formula IA or pharmaceutically acceptable salt thereoffurther comprises nirogacestat hydrobromide. In some aspects, thepharmaceutical composition comprising a compound of Formula IA orpharmaceutically acceptable salt thereof further comprises nirogacestatdihydrobromide.

The disclosure further relates to a pharmaceutical compositioncomprising a compound which is a compound of Formula IB

or a pharmaceutically acceptable salt thereof. In some aspects, thecompound of Formula IB or pharmaceutically acceptable salt thereof inthe pharmaceutical composition is present in an amount of about 1 μg toabout 500 μg. In some aspects, the compound of Formula IB orpharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 2 μg to about 500 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 3 μg to about 500 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 4 μg to about 500 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 5 μg to about 500 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 6 μg to about 475 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 6 μg to about 450 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 7 μg to about 425 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 7 μg to about 400 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 8 μg to about 375 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 8 μg to about 350 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 9 μg to about 325 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 9 μg to about 300 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 275 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 250 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 225 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 200 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 175 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 150 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 125 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 100 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 90 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 80 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 70 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 60 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 50 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 11 μg to about 50 μg. In some aspects, the compound of FormulaIB or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 12 μg to about 50 μg. Insome aspects, the compound of Formula IB or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 12.5 μg to about 50 μg.

In some aspects, the pharmaceutical composition comprising a compound ofFormula IB further comprises a gamma-secretase inhibitor selected fromthe group consisting of nirogacestat, or a pharmaceutically acceptablesalt thereof, crenigacestat, or a pharmaceutically acceptable saltthereof, AL101, or a pharmaceutically acceptable salt thereof, AL102, ora pharmaceutically acceptable salt thereof, semagacestat, or apharmaceutically acceptable salt thereof, avagacestat, or apharmaceutically acceptable salt thereof, and ianabecestat, or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising a compound of Formula IB furthercomprises nirogacestat, or pharmaceutically acceptable salt thereof. Insome aspects, the pharmaceutical composition comprising a compound ofFormula IB further comprises crenigacestat, or pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising a compound of Formula IB further comprises AL101, orpharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising a compound of Formula IB furthercomprises AL102, or pharmaceutically acceptable salt thereof. In someaspects, the pharmaceutical composition comprising a compound of FormulaIB further comprises semagacestat, or pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition comprising acompound of Formula IB further comprises avagacestat, orpharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising a compound of Formula IB furthercomprises ianabecestat, or pharmaceutically acceptable salt thereof. Insome aspects, the pharmaceutical composition comprising a compound ofFormula IB or pharmaceutically acceptable salt thereof further comprisesnirogacestat hydrobromide. In some aspects, the pharmaceuticalcomposition comprising a compound of Formula IB or pharmaceuticallyacceptable salt thereof further comprises nirogacestat dihydrobromide.

The disclosure further relates to a pharmaceutical compositioncomprising a compound which is a compound of Formula IC

or a pharmaceutically acceptable salt thereof. In some aspects, thecompound of Formula IC or pharmaceutically acceptable salt thereof inthe pharmaceutical composition is present in an amount of about 1 μg toabout 500 μg. In some aspects, the compound of Formula IC orpharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 2 μg to about 500 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 3 μg to about 500 μg. In some aspects, the compound of FormulaIC or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 4 μg to about 500 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 5 μg to about 500 μg. In some aspects, the compound of FormulaIC or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 6 μg to about 475 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 6 μg to about 450 μg. In some aspects, the compound of FormulaIC or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 7 μg to about 425 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 7 μg to about 400 μg. In some aspects, the compound of FormulaIC or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 8 μg to about 375 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 8 μg to about 350 μg. In some aspects, the compound of FormulaIC or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 9 μg to about 325 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 9 μg to about 300 μg. In some aspects, the compound of FormulaIC or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 275 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 250 μg. In some aspects, the compound of FormulaIC or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 225 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 200 μg. In some aspects, the compound of FormulaIC or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 175 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 150 μg. In some aspects, the compound of FormulaIC or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 125 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 100 μg. In some aspects, the compound of FormulaIC or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 90 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 80 μg. In some aspects, the compound of FormulaIC or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 70 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 10 μg to about 60 μg. In some aspects, the compound of FormulaIC or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 10 μg to about 50 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 11 μg to about 50 μg. In some aspects, the compound of FormulaIC or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 12 μg to about 50 μg. Insome aspects, the compound of Formula IC or pharmaceutically acceptablesalt thereof in the pharmaceutical composition is present in an amountof about 12.5 μg to about 50 μg.

In some aspects, the pharmaceutical composition comprising a compound ofFormula IC further comprises a gamma-secretase inhibitor selected fromthe group consisting of nirogacestat, or a pharmaceutically acceptablesalt thereof, crenigacestat, or a pharmaceutically acceptable saltthereof, AL101, or a pharmaceutically acceptable salt thereof, AL102, ora pharmaceutically acceptable salt thereof, semagacestat, or apharmaceutically acceptable salt thereof, avagacestat, or apharmaceutically acceptable salt thereof, and ianabecestat, or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising a compound of Formula IC furthercomprises nirogacestat, or pharmaceutically acceptable salt thereof. Insome aspects, the pharmaceutical composition comprising a compound ofFormula IC further comprises crenigacestat, or pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprising a compound of Formula IC further comprises AL101, orpharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising a compound of Formula IC furthercomprises AL102, or pharmaceutically acceptable salt thereof. In someaspects, the pharmaceutical composition comprising a compound of FormulaIC further comprises semagacestat, or pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition comprising acompound of Formula IC further comprises avagacestat, orpharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprising a compound of Formula IC furthercomprises ianabecestat, or pharmaceutically acceptable salt thereof. Insome aspects, the pharmaceutical composition comprising a compound ofFormula IC or pharmaceutically acceptable salt thereof further comprisesnirogacestat hydrobromide. In some aspects, the pharmaceuticalcomposition comprising a compound of Formula IC or pharmaceuticallyacceptable salt thereof further comprises nirogacestat dihydrobromide.

In some aspects, the compound of Formula I, Formula IA, Formula IB, andFormula IC in the pharmaceutical composition is in the free base form.

In some aspects, the compound of Formula I, Formula IA, Formula IB, andFormula IC in the pharmaceutical composition is in a pharmaceuticallyacceptable salt form. In some aspects, the pharmaceutically acceptablesalt form of the compound of Formula I, Formula IA, Formula IB, andFormula IC in the pharmaceutical composition is a hydrobromide saltform. In some aspects, the pharmaceutically acceptable salt form of thecompound of Formula I, Formula IA, Formula IB, and Formula IC in thepharmaceutical composition is a dihydrobromide salt form.

In some aspects, the pharmaceutical composition comprising the compoundof Formula I is an oral tablet that additionally comprises apharmaceutically acceptable carrier. For oral administration, knowncarriers can be included in the pharmaceutical composition. For example,microcrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (preferably corn, potato or tapioca starch),methylcellulose, alginic acid and certain complex silicates, togetherwith granulation binders such as polyvinylpyrrolidone, sucrose, gelatinand acacia, can be included in a tablet. Additionally, lubricatingagents such as magnesium stearate, sodium lauryl sulfate and talc areoften useful for tabletting purposes. Solid compositions of a similartype may also be employed as fillers in gelatin capsules. Preferredmaterials in this connection include lactose or milk sugar as well ashigh molecular weight polyethylene glycols. When aqueous suspensionsand/or elixirs are desired for oral administration, the activeingredient may be combined with various sweetening or flavoring agents,coloring matter or dyes, and, if so desired, emulsifying and/orsuspending agents as well, together with such diluents as water,ethanol, propylene glycol, glycerin and various like combinationsthereof.

For parenteral administration, solutions containing Compound 1 can beprepared in either sesame or peanut oil, in aqueous propylene glycol, orin sterile water or saline. The aqueous solutions should be suitablybuffered (preferably pH greater than 8) if necessary and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theseaqueous solutions are suitable for intravenous injection purposes. Theoily solutions are suitable for intraarticular, intramuscular andsubcutaneous injection purposes. The preparation of all these solutionsunder sterile conditions is readily accomplished by standardpharmaceutical techniques well known to those skilled in the art.

In one aspect, the tablet comprises the compound of Formula I and about25 mg to about 400 mg of nirogacestat, or pharmaceutically acceptablesalt thereof. In one aspect, the tablet comprises about 25 mg, about 30mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg,about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185mg, about 190 mg, about 195 mg, about 200 mg, about 225 mg, about 250mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375mg, or about 400 mg of nirogacestat, or a pharmaceutically acceptablesalt thereof. In one aspect, the tablet comprises about 50 mg ofnirogacestat, or a pharmaceutically acceptable salt thereof. In oneaspect, the tablet comprises about 100 mg of nirogacestat, or apharmaceutically acceptable salt thereof. In one aspect, the tabletcomprises about 150 mg of nirogacestat, or pharmaceutically acceptablesalt thereof.

In one aspect, the tablet comprises the compound of Formula I and about25 mg to about 400 mg of nirogacestat hydrobromide. In one aspect, thetablet comprises about 25 mg, about 30 mg, about 35 mg, about 40 mg,about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg,about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg,about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg,about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg,about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg,about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg,about 325 mg, about 350 mg, about 375 mg, or about 400 mg ofnirogacestat hydrobromide. In one aspect, the tablet comprises about 50mg of nirogacestat hydrobromide. In one aspect, the tablet comprisesabout 100 mg of nirogacestat hydrobromide. In one aspect, the tabletcomprises about 150 mg of nirogacestat hydrobromide.

In one aspect, the tablet comprises the compound of Formula I and about25 mg to about 400 mg of nirogacestat dihydrobromide. In one aspect, thetablet comprises about 25 mg, about 30 mg, about 35 mg, about 40 mg,about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg,about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg,about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg,about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg,about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg,about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg,about 325 mg, about 350 mg, about 375 mg, or about 400 mg ofnirogacestat dihydrobromide. In one aspect, the tablet comprises about50 mg of nirogacestat dihydrobromide. In one aspect, the tabletcomprises about 100 mg of nirogacestat dihydrobromide. In one aspect,the tablet comprises about 150 mg of nirogacestat dihydrobromide.

IV. Methods of Treatment

The pharmaceutical composition comprising a compound of Formula I can beadministered to modulate or inhibit the Notch signaling pathway inorganisms, including humans. Notch signaling is frequently elevated in avariety of human tumors (including, but not limited to breast, prostate,pancreas and T-cell acute lymphoblastic leukemia). Accordingly, thepharmaceutical composition comprising a compound of Formula I can beadministered to treat a subject with tumors or cancer, including, butnot limited to desmoid tumors, multiple myeloma, adenoid cysticcarcinoma, and T-cell acute lymphoblastic leukemia. In one aspect, thepharmaceutical composition comprising a compound of Formula I can beadministered to treat a subject with tumors or cancer, including, butnot limited to desmoid tumors, multiple myeloma, adenoid cysticcarcinoma, and T-cell acute lymphoblastic leukemia. In one aspect, thepharmaceutical composition comprising a compound of Formula I isadministered to treat a subject having tumors, including desmoid tumors.In one aspect, the pharmaceutical composition comprising a compound ofFormula I is administered to treat a subject with a cancer having amutation in a Notch pathway gene. In one aspect, the pharmaceuticalcomposition comprising a compound of Formula I is administered to treata subject having multiple myeloma. In some aspects, the pharmaceuticalcomposition comprising a compound of Formula I is administered to treata subject having adenoid cystic carcinoma. In some aspects, thepharmaceutical composition comprising a compound of Formula I isadministered to treat a subject having T-cell acute lymphoblasticleukemia.

EXAMPLES

The following synthetic examples are illustrative, but not limiting, ofthe methods described herein. Other suitable modifications andadaptations of the variety of conditions and parameters normallyencountered in the field, and which are obvious to those skilled in theart, are within the spirit and scope of the invention.

Synthetic Example 1

2-(2-chloro-4-fluorophenyl)acetic acid is reacted with oxalyl chloridein dichloromethane at 0° C. in the presence of dimethylformamide. Theresulting acid chloride is reacted with aluminum chloride and ethylenegas at 0° C. After quenching the mixture with water, the dichloromethanesolution is distilled and replaced with tert-butyl methyl ether. Theresulting slurry is cooled to 0° C. and filtered to isolate8-chloro-6-fluoro-3,4-dihydronaphthalen-2(1H)-one.

Synthetic Example 2

8-chloro-6-fluoro-3,4-dihydronaphthalen-2(1H)-one is added to aphosphate buffer solution (pH 7-8) and reacted with isopropylamine inthe presence of an amino transaminase and pyridoxal-5-phosphatemonohydrate at 25° C. The resulting phosphoric acid salt is filtered andwashed with acetone to isolate(S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine phosphoricacid salt.

Synthetic Example 3

(S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine phosphoricacid salt is added to tert-butyl methyl ether and then freebased withaqueous sodium hydroxide. The tert-butyl methyl ether is then removed bydistillation and replaced with dichloromethane. Tert-butyl(R)-2-hydroxypentanoate is dissolved in dichloromethane withN,N-diisopropylethylamine and then reacted with trifluromethanesulfonicanhydride at −25° C. The resulting triflate is reacted with the freebaseamine dichloromethane solution in the presence ofN,N-diisopropylethylamine at 25° C. The mixture is quenched with aqueouspotassium carbonate and the dichloromethane is removed by distillationand replaced with 1,4-dioxane. Hydrogen chloride solution in 1,4-dioxaneis added to the mixture and the resulting hydrochloride salt is filteredand rinsed with 1,4-dioxane to isolate(S)-tert-butyl-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)pentanoatehydrochloride.

Synthetic Example 4

(S)-tert-butyl-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)pentanoatehydrochloride is added to a mixture of isopropanol and water and reactedwith hydrochloric acid at 60° C. After the reaction is complete, themixture is adjusted to a pH of ˜7.0 with aqueous sodium hydroxide. Theresulting slurry is filtered and washed with isopropanol to isolate(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)pentanoicacid.

Synthetic Example 5

(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)pentanoicacid is added to acetonitrile and pyridine hydrobromide and reacted withN,N-Carbonyldiimidazole at 25° C. After the reaction is complete,triethylamine is added to the mixture.1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-aminedihydrobromide is added to acetonitrile, cooled to −8° C., and freebasedwith triethylamine. The N,N-Carbonyldiimidazole reaction mixture isadded to the freebased1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-amine mixtureand reacted at −8° C. After reaction completion, hydrobromic acid isadded at 40° C. and the resulting solution is adjusted to pH 2.8 withtriethylamine. The resulting slurry is filtered and washed withacetonitrile to isolate(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide.(S)-2-(((S)-8-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide was further purified through crystallization bydissolving in ethanol and water with hydrobromic acid followed byaddition of triethylamine. The resulting slurry was cooled, filtered,and rinsed with ethanol. Analytical Data: ¹H NMR (400 MHz, DMSO-d₆):11.33 (s, 1H), 9.35 (bd, 2H), 7.95 (bd, 2H), 7.76 (s, 1H), 7.55 (s, 1H),7.32 (d, 1H), 7.06 (d, 1H), 4.24 (m, 1H), 3.50 (m, 3H), 3.31 (m, 1H),2.92 (m, 1H), 2.80 (m, 2H), 2.55 (m, 2H), 2.19 (m, 1H), 1.85 (m, 3H),1.64 (d, 6H), 1.31 (m, 2H), 0.91 (t, 3H), 0.87 (s, 9H); MS m/z: 506.30(M+H).

Synthetic Example 6

2-(4-chloro-2-fluorophenyl)acetic acid is reacted with oxalyl chloridein dichloromethane at 0° C. in the presence of dimethylformamide. Theresulting acid chloride is reacted with aluminum chloride and ethylenegas at 0° C. After quenching the mixture with water, the dichloromethanesolution is distilled and replaced with tert-butyl methyl ether. Theresulting slurry is cooled to 0° C. and filtered to isolate6-chloro-8-fluoro-3,4-dihydronaphthalen-2(1H)-one.

Synthetic Example 7

6-chloro-8-fluoro-3,4-dihydronaphthalen-2(1H)-one is added to aphosphate buffer solution (pH 7-8) and reacted with isopropylamine inthe presence of an amino transaminase and pyridoxal-5-phosphatemonohydrate at 25° C. The resulting phosphoric acid salt is filtered andwashed with acetone to isolate(S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine phosphoricacid salt.

Synthetic Example 8

(S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine phosphoricacid salt is added to tert-butyl methyl ether and then freebased withaqueous sodium hydroxide. The tert-butyl methyl ether is then removed bydistillation and replaced with dichloromethane. Tert-butyl(R)-2-hydroxypentanoate is dissolved in dichloromethane withN,N-diisopropylethylamine and then reacted with trifluromethanesulfonicanhydride at −25° C. The resulting triflate is reacted with the freebaseamine dichloromethane solution in the presence ofN,N-diisopropylethylamine at 25° C. The mixture is quenched with aqueouspotassium carbonate and the dichloromethane is removed by distillationand replaced with 1,4-dioxane. Hydrogen chloride solution in 1,4-dioxaneis added to the mixture and the resulting hydrochloride salt is filteredand rinsed with 1,4-dioxane to isolate(S)-tert-butyl-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)pentanoatehydrochloride.

Synthetic Example 9

(S)-tert-butyl-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)pentanoatehydrochloride is added to a mixture of isopropanol and water and reactedwith hydrochloric acid at 60° C. After the reaction is complete, themixture is adjusted to a pH of ˜7.0 with aqueous sodium hydroxide. Theresulting slurry is filtered and washed with isopropanol to isolate(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)pentanoicacid.

Synthetic Example 10

(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)pentanoicacid is added to acetonitrile and pyridine hydrobromide and reacted withN,N-Carbonyldiimidazole at 25° C. After the reaction is complete,triethylamine is added to the mixture.1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-aminedihydrobromide is added to acetonitrile, cooled to −8° C., and freebasedwith triethylamine. The N,N-Carbonyldiimidazole reaction mixture isadded to the freebased1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-amine mixtureand reacted at −8° C. After reaction completion, hydrobromic acid isadded at 40° C. and the resulting solution is adjusted to pH 2.8 withtriethylamine. The resulting slurry is filtered and washed withacetonitrile to isolate(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide.(S)-2-(((S)-6-chloro-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide was further purified through crystallization bydissolving in ethanol and water with hydrobromic acid followed byaddition of triethylamine. The resulting slurry was cooled, filtered,and rinsed with ethanol. Analytical Data: ¹H NMR (400 MHz, DMSO-d₆):11.30 (s, 1H), 9.63 (bs, 1H), 9.38 (bs, 1H), 8.20 (bs, 2H), 7.77 (s,1H), 7.56 (s, 1H), 7.24 (d, 1H), 7.10 (s, 1H), 4.27 (m, 1H), 3.65 (m,3H), 3.53 (m, 2H), 3.28 (m, 1H), 2.95 (m, 1H), 2.83 (m, 2H), 2.25 (m,1H), 1.88 (m, 3H), 1.66 (d, 6H), 1.33 (m, 2H), 0.90 (t, 3H), 0.86 (s,9H); MS m/z: 506.30 (M+H).

Synthetic Example 11

2-(3-chloro-4-fluorophenyl)acetic acid is reacted with oxalyl chloridein dichloromethane at 0° C. in the presence of dimethylformamide. Theresulting acid chloride is reacted with aluminum chloride and ethylenegas at 0° C. After quenching the mixture with water, the dichloromethanesolution is distilled and replaced with tert-butyl methyl ether. Theresulting slurry is cooled to 0° C. and filtered to isolate7-chloro-6-fluoro-3,4-dihydronaphthalen-2(1H)-one.

Synthetic Example 12

7-chloro-6-fluoro-3,4-dihydronaphthalen-2(1H)-one is added to aphosphate buffer solution (pH 7-8) and reacted with isopropylamine inthe presence of an amino transaminase and pyridoxal-5-phosphatemonohydrate at 25° C. The resulting phosphoric acid salt is filtered andwashed with acetone to isolate(S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine phosphoricacid salt.

Synthetic Example 13

(S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine phosphoricacid salt is added to tert-butyl methyl ether and then freebased withaqueous sodium hydroxide. The tert-butyl methyl ether is then removed bydistillation and replaced with dichloromethane. Tert-butyl(R)-2-hydroxypentanoate is dissolved in dichloromethane withN,N-diisopropylethylamine and then reacted with trifluromethanesulfonicanhydride at −25° C. The resulting triflate is reacted with the freebaseamine dichloromethane solution in the presence ofN,N-diisopropylethylamine at 25° C. The mixture is quenched with aqueouspotassium carbonate and the dichloromethane is removed by distillationand replaced with 1,4-dioxane. Hydrogen chloride solution in 1,4-dioxaneis added to the mixture and the resulting hydrochloride salt is filteredand rinsed with 1,4-dioxane to isolate(S)-tert-butyl-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)pentanoatehydrochloride.

Synthetic Example 14

(S)-tert-butyl-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)pentanoatehydrochloride is added to a mixture of isopropanol and water and reactedwith hydrochloric acid at 60° C. After the reaction is complete, themixture is adjusted to a pH of ˜7.0 with aqueous sodium hydroxide. Theresulting slurry is filtered and washed with isopropanol to isolate(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)pentanoicacid.

Synthetic Example 15

(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)pentanoicacid is added to acetonitrile and pyridine hydrobromide and reacted withN,N-Carbonyldiimidazole at 25° C. After the reaction is complete,triethylamine is added to the mixture.1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-aminedihydrobromide is added to acetonitrile, cooled to −8° C., and freebasedwith triethylamine. The N,N-Carbonyldiimidazole reaction mixture isadded to the freebased1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-amine mixtureand reacted at −8° C. After reaction completion, hydrobromic acid isadded at 40° C. and the resulting solution is adjusted to pH 2.8 withtriethylamine. The resulting slurry is filtered and washed withacetonitrile to isolate(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide.(S)-2-(((S)-7-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamidedihydrobromide was further purified through crystallization bydissolving in ethanol and water with hydrobromic acid followed byaddition of triethylamine. The resulting slurry was cooled, filtered,and rinsed with ethanol. Analytical Data: ¹H NMR (400 MHz, DMSO-d₆):11.25 (s, 1H), 9.41 (bs, 1H), 9.26 (bs, 1H), 8.06 (bs, 2H), 7.77 (s,1H), 7.55 (s, 1H), 7.32 (d, 1H), 7.20 (d, 1H), 4.24 (m, 1H), 3.52 (m,2H), 3.28 (m, 1H), 3.15 (m, 2H) 2.90 (m, 2H), 2.78 (m, 1H), 2.53 (m,1H), 2.25 (m, 1H), 1.89 (m, 3H), 1.66 (d, 6H), 1.33 (m, 2H), 0.91 (t,3H), 0.86 (s, 9H); MS m/z: 506.30 (M+H).

What is claimed is:
 1. A method of treating a desmoid tumor in a patientin need thereof comprising administering a pharmaceutical compositioncomprising a compound of Formula IA

or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein the compound of Formula IA or pharmaceutically acceptable saltthereof in the pharmaceutical composition is present in an amount ofabout 1 μg to about 200 μg.
 3. The method of claim 1, wherein thecompound of Formula IA or pharmaceutically acceptable salt thereof inthe pharmaceutical composition is present in an amount of about 1 μg toabout 150 μg.
 4. The method of claim 1, wherein the compound of FormulaIA or pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 1 μg to about 100 μg. 5.The method of claim 1, wherein the compound of Formula IA orpharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 1 μg to about 50 μg.
 6. Themethod of claim 1, wherein the pharmaceutical composition furthercomprises nirogacestat or a pharmaceutically acceptable salt thereof. 7.The method of claim 6, wherein the compound of Formula IA orpharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 1 μg to about 200 μg. 8.The method of claim 7, wherein the pharmaceutical composition comprises50 mg nirogacestat or a pharmaceutically acceptable salt thereof.
 9. Themethod of claim 6, wherein the compound of Formula IA orpharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 1 μg to about 150 μg. 10.The method of claim 9, wherein the pharmaceutical composition comprises50 mg nirogacestat or a pharmaceutically acceptable salt thereof. 11.The method of claim 6, wherein the compound of Formula IA orpharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 1 μg to about 100 μg. 12.The method of claim 11, wherein the pharmaceutical composition comprises50 mg nirogacestat or a pharmaceutically acceptable salt thereof. 13.The method of claim 6, wherein the compound of Formula IA orpharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is present in an amount of about 1 μg to about 50 μg. 14.The method of claim 13, wherein the pharmaceutical composition comprises50 mg nirogacestat or a pharmaceutically acceptable salt thereof.